Susceptibility of podocytes to palmitic acid is regulated by fatty acid oxidation and inversely depends on acetyl-CoA carboxylases 1 and 2

Am J Physiol Renal Physiol. 2014 Feb 15;306(4):F401-9. doi: 10.1152/ajprenal.00454.2013. Epub 2013 Dec 11.

Abstract

Type 2 diabetes is characterized by dyslipidemia with elevated free fatty acids (FFAs). Loss of podocytes is a hallmark of diabetic nephropathy, and podocytes are susceptible to saturated FFAs, which induce endoplasmic reticulum (ER) stress and podocyte death. Genome-wide association studies indicate that expression of acetyl-CoA carboxylase (ACC) 2, a key enzyme of fatty acid oxidation (FAO), is associated with proteinuria in type 2 diabetes. Here, we show that stimulation of FAO by aminoimidazole-4-carboxamide-1β-D-ribofuranoside (AICAR) or by adiponectin, activators of the low-energy sensor AMP-activated protein kinase (AMPK), protects from palmitic acid-induced podocyte death. Conversely, inhibition of carnitine palmitoyltransferase (CPT-1), the rate-limiting enzyme of FAO and downstream target of AMPK, augments palmitic acid toxicity and impedes the protective AICAR effect. Etomoxir blocked the AICAR-induced FAO measured with tritium-labeled palmitic acid. The beneficial effect of AICAR was associated with a reduction of ER stress, and it was markedly reduced in ACC-1/-2 double-silenced podocytes. In conclusion, the stimulation of FAO by modulating the AMPK-ACC-CPT-1 pathway may be part of a protective mechanism against saturated FFAs that drive podocyte death. Further studies are needed to investigate the potentially novel therapeutic implications of these findings.

Keywords: AMPK; apoptosis; diabetic nephropathy; palmitic acid; β-oxidation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism
  • Acetyl-CoA Carboxylase / metabolism*
  • Aminoimidazole Carboxamide / analogs & derivatives
  • Aminoimidazole Carboxamide / pharmacology
  • Animals
  • Carnitine O-Palmitoyltransferase / antagonists & inhibitors
  • Carnitine O-Palmitoyltransferase / metabolism
  • Cells, Cultured
  • Fatty Acids / metabolism*
  • Lipid Metabolism / drug effects*
  • Mice
  • Palmitic Acid / pharmacology*
  • Podocytes / drug effects*
  • Podocytes / metabolism
  • Ribonucleotides / pharmacology

Substances

  • Fatty Acids
  • Ribonucleotides
  • Palmitic Acid
  • Aminoimidazole Carboxamide
  • Carnitine O-Palmitoyltransferase
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase
  • AICA ribonucleotide